Influenza viruses consist of eight pieces of single stranded RNA, packaged in orderly fashion within the virion. Each piece codes for one of the major viral proteins. The replication complex is enclosed within a membrane composed of matrix protein associated with a lipid bilayer. Embedded in the lipid bilayer are two surface glycoprotein spikes, hemagglutinin (HA) and the enzyme neuraminidase (NA). All of the viral genes have been cloned and the three-dimensional structures of the surface glycoproteins have been determined.
Despite the wealth of information available, influenza remains a potentially devastating disease of man, lower mammals, and birds. No effective vaccine exists and no cure is available once the infection has set in.
Influenza viruses continually undergo antigenic variation in the two surface antigens, HA and NA, toward which neutralizing antibodies are directed. For this reason, vaccines and a subject's natural immune system have not been very effective. Attention is now being directed to finding other potential antiviral agents acting at other sites of the virion. This invention is directed to novel compounds which are useful in inhibiting the viral surface enzyme NA.
Furthermore, many other organisms carry NA. Many of these NA-possessing organisms are also major pathogens of man and/or mammals, including Vibrata choleral, Clostridium perfringes, Streptococcus pneumonia, Arthrobacter sialophilas, and other viruses such as parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, and Sendai virus. Compounds of this invention are also directed to inhibiting NA of these organisms.
In viruses, NA exists as a tetramer made of four roughly spherical subunits and a centrally-attached stalk containing a hydrophobic region by which it is embedded in the organism's membrane. Several roles have been suggested for NA. The enzyme catalyzes cleavage of the .alpha.-ketosidic linkage between terminal sialic acid and an adjacent sugar residue. Removal of the sialic acid lowers the viscosity and permits access of the virus to the epithelial cells. NA also destroys the HA receptor on the host cell, thus allowing elution of progeny virus particles from infected cells. In general, the role of NA is thought to be for the mobility of the virus both to and from the site of infections. Compounds that inhibit neuraminidase's activity may protect a subject from infection and/or cure a subject once infection has set in. It is a further object of this invention to provide a method of using compounds of this invention for treating and/or curing a viral infection.
Analogs of neuraminic acid, such as 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) and its derivatives are known to inhibit HA in vitro; however, these compounds are inactive in vivo. Palese and Schulman, in Chemoprophylaxis and Virus Infection of the Upper Respiratory Tract, Vol. 1 (J. S. Oxford, Ed.), CRC Press, 1977, at PS 189-205.
Von Itzstein et al. describes cyclohexane analogs of .alpha.-D-neuraminic acid of the formula: ##STR2## wherein: A is O, C, or S in Formula (a), and N or C in Formula (b);
R.sup.1 is CO.sub.2 H, PO.sub.3 H.sub.2, NO.sub.2, SO.sub.2, SO.sub.3 H, tetrazolyl-, CH.sub.2 CHO, CHO, or CH(CHO).sub.2 ; PA1 R.sup.2 is H, OR.sup.6, F, Cl, Br, CN, NHR.sup.6, SR.sup.6 or CH.sub.2 X, where X is NHR.sup.6 halogen, or OR.sup.6 ; PA1 R.sup.3 and R.sup.3' are H, CN, NHR.sup.6, N.sub.3, SR.sup.6, .dbd.NOR.sup.6, OR.sup.6, guanidino, NR.sup.6 ; PA1 R.sup.4 is NHR.sup.6, SR.sup.6, OR.sup.6, CO.sub.2 R.sup.6, NO.sub.2, C(R.sup.6).sub.3, CH.sub.2 CO.sub.2 R.sup.6, CH.sub.2 NO.sub.2, or CH.sub.2 NHR.sup.6 ; PA1 R.sup.5 is CH.sub.2 YR.sup.6, CHYR.sup.6 CH.sub.2 YR.sup.6 or CHYR.sup.6 CHYR.sup.6 CH.sub.2 YR.sup.6 ; PA1 R.sup.6 is H, acyl, alkyl, allyl, or aryl; PA1 Y is O, S, NH, or H, and pharmaceutical salts thereof; useful as antiviral agents. This reference does not disclose aromatic derivatives of the present invention. PA1 m is 0-3; PA1 p is 0-1; PA1 R.sup.1 is selected from the group consisting of --CO.sub.2 H, --SO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2, and tetrazolyl; PA1 R.sup.2 is selected from the group consisting of H, --OH, and --NH.sub.2 ; PA1 R.sup.3 is selected independently at each occurrence from the group consisting of --OR, --N(R).sub.2, --N.sub.3, --NHC(R.sup.6)NH.sub.2, --CN --C(R.sup.6)NH.sub.2, H, --C(R)(.dbd.N)NHC(.dbd.NH)NH.sub.2, --C(.dbd.N)RC(.dbd.NH)NH.sub.2, NHCN, and CH.dbd.NOH; PA1 R.sup.4 is selected from the group consisting of H, --OR, --(CH.sub.2).sub.p NHR.sup.7 and --C(O)NHR.sup.8 ; PA1 R.sup.5 is selected from the group consisting of H, --R.sup.3, --(CH(R.sup.3).sub.n).sub.m CH.sub.2 R.sup.3, --NHC(R.sup.6)NH.sub.2, --CH.dbd.CHCH.sub.2 R.sup.3, NHCN, and CH.dbd.NOH; PA1 R.sup.6 is selected from the group consisting of .dbd.NH, .dbd.NOH, .dbd.NCN, .dbd.O, and .dbd.S; PA1 R.sup.7 is selected from the group consisting of --C(.dbd.Y)R.sup.8, --S(O.sub.2)R, --C(O)OR.sup.8, --C(.dbd.Y)NHR.sup.8, and --CH.sub.2 C(.dbd.Y)R.sup.8 ; PA1 R.sup.8 is selected from the group consisting of C.sub.1 -C.sub.4 linear or branched alkyl substituted with 0-3 halogens on each carbon; PA1 R is selected from the group consisting of H, C.sub.1 -C.sub.4 linear or branched alkyl, C.sub.1 -C.sub.4 linear or branched alkyl-OH, C.sub.1 -C.sub.4 linear or branched alkyl-NH.sub.2 ; PA1 Y is O or S; PA1 with the following provisos: PA1 R.sup.1 is CO.sub.2 H; PA1 R.sup.2 is H; PA1 R.sup.3 is selected from the group consisting of H, --OR, --NHC(R.sup.6)NH.sub.2, NHCN, and CH.dbd.NOH; PA1 R.sup.4 is selected from the group consisting of H, --OR, --(CH.sub.2).sub.p NHR.sup.7, and --C(O)NHR.sup.8 ; PA1 R.sup.5 is selected from the group consisting of H, --CH(R.sup.3).sub.2 CH.sub.2 OR, --CH.sub.2 OR, --NHC(R.sup.6)NH.sub.2, --CH.dbd.CHCH.sub.2 OR, --NHCN, and CH.dbd.NOH; PA1 R.sup.6 is selected from the group consisting of .dbd.NH, .dbd.NOH, .dbd.NCN, .dbd.O, and .dbd.S; PA1 R.sup.7 is selected from the group consisting of --C(.dbd.Y)R.sup.8, --S(O.sub.2)R, --C(O)OR.sup.8, --C(.dbd.Y)NHR.sup.8, and --CH.sub.2 C(.dbd.Y)R.sup.8 ; PA1 R.sup.8 is selected from the group consisting of C.sub.1 -C.sub.4 linear or branched alkyl substituted with 0-3 halogens on each carbon; PA1 m is 0-2; and PA1 p is 0, with the following provisos: PA1 R.sup.1 is CO.sub.2 H; PA1 R.sup.2 is H; PA1 R.sup.3 is selected from the group consisting of H, --OH, --NHC(.dbd.NH)NH.sub.2, NHCN, and CH.dbd.NOH; PA1 R.sup.4 is H, --OH, --OCH.sub.3, --NHCOCH.sub.3, --NHSO.sub.2 CH.sub.3, and C(O)NHCH.sub.3 ; PA1 R.sup.5 is H, --CH.sub.2 CH(OH)CH.sub.2 OH, --CH.sub.2 OH, --NHC(.dbd.NH)NH.sub.2, and --CH.dbd.CHCH.sub.2 OH, --NHCN, CH.dbd.NOH; and PA1 m is 0-2; PA1 with the following provisos: PA1 Phenylguanidine; PA1 1-Phenylbiguanide; PA1 4-Acetylaminobenzoic acid; PA1 4-Acetylaminobenzenesulfonic acid; PA1 4-Acetylaminophenylphosphoric acid; PA1 4-(Trifluoroacetamido)benzoic acid; PA1 4-Thioacetamidobenzoic acid; PA1 4-[(Methylsulfonyl)amino]benzoic acid; PA1 3-Guanidinobenzoic acid; PA1 3-[Amino(cyanoimino)methyl]aminobenzoic acid; PA1 3-Cyanoaminobenzoic acid; PA1 3-(2-Amino-2-imino)ethylbenzoic acid; PA1 4-(Acetamino)phenylacetic acid; PA1 4-(Methylaminocarbonyl)benzoic acid; PA1 4-Acetylamino-3-hydroxymethylbenzoic acid; PA1 .beta.-(2-N-Acetylamino-5-carboxyphenyl)ethanol PA1 4-Acetylamino-3-(2',3'-dihydroxypropyl)benzoic acid; PA1 4-Acetylamino-3-aminobenzoic acid; PA1 4-Acetylamino-3-[(aminoiminomethyl)amino]benzoic acid; PA1 3-[(Aminoiminomethyl)amino]-4-(2-methylpropionylamino)benzoic acid; PA1 4-Acetylamino-3-[(hydroxylimino)methyl]benzoic acid; PA1 3-[(Aminoiminomethyl)amino]-4-[(methylsulfonyl)amino]benzoic acid; PA1 3-[(N-Hydroxyimino)methyl]-4-[(methylsulfonyl)amino]benzoic acid; PA1 3-[((Aminoimino)methyl)amino]-4-methoxybenzoic acid; PA1 3-[(Aminoiminomethyl)amino]-4-hydroxybenzoic acid; PA1 3,5-Bis-[(aminoiminomethyl)amino]benzoic acid; PA1 3-Amino-5-{[(aminoimino)methyl]amino}benzoic acid; PA1 3-[(Aminoiminomethyl)amino]-5-[(N-hydroxylimino)methyl]benzoic acid; and PA1 3-[(Aminoiminomethyl)amino-5-hydroxymethyl)-4-(methylsulfonyl)aminobenzoic acid.